In patients with the nonobstructive form of hypertrophic cardiomyopathy, a markedly hypertrophied noncompliant left ventricle is believed to be largely responsible for diastolic dysfunction and cardiac symptoms. However, we have recently shown that left ventricular hypertrophy cardiomyopathy who have only mild left ventricular hyperthrohy. This finding would suggest that factors other than hypertrophy may play a role in the genesis of left ventricular dysfunction in patients with this disease. To identify the pathogenetic mechanisms that, in the absence of marked left ventricular hypertrophy and subaortic gradient, may be responsible for left ventricular dysfunction in hypertrophic cardiomyopathy, we have analyzed the long-term clinical course of a population of patients with nonobstructive form of this disease and mild localized left ventricular hypertrophy. Fourty-four such patients were initially evaluated. Twelve of the 44 patients, who were identified as having severe cardiac symptoms (New York Heart Association functional class III or IV), comprise our study group. Radionuclide angiography showed depressed left ventricular systolic function in eight of the 12 patients (ejection fraction less than 45) and impaired diastolic filling in 10 (peak filling rate less than 2.5 EDV/sec). Long term M-mode echocardiographic follow-up (2-11 years; mean 6 years) available in 10 of the 12 patients, demonstrated progressive ventricular septal thinning (from 23\plus/minus\5mm to 19\plus/minus\4mm; p less than 0.02) and increase in left ventricular end-diastolic dimension (from 39\plus/minus\6mm to 46\plus/minus\5mm; p less than 0.005). Hence, severe cardiac symptoms may occur in patients with nonobstructive hypertrophic cardiomyopathy who have only mild localized left ventricular hypertrophy. Furthermore, the presence of progressive left ventricular wall thinning and cavity enlargement associated with depressed systolic function in these patients suggests that extensive myocardial scarring could be the determinant of their functional deterioration.